Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats.
Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains undefined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg i.p.) were assessed by whole body plethysmography during normoxia, hypoxia (10% O2), and hyperoxia (100% O2) in unrestrained Sprague-Dawley rats. A sustained expiratory time increase occurred within 8-10 min of injection in room air[mean 44.8 +/- 5.2 (SE) % ], was similar to expiratory time prolongations after Ro-32-0432 administration during 100% O2 (45.5 +/- 8.1%; not significant), and was associated with mild minute ventilation (VE) decreases. Hypercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32-0432. During 10% O2, VE increased from 122.6 +/- 15.6 to 195.7 +/- 10.1 ml/min in vehicle-treated rats (P < 0.001). In contrast, marked attenuation of VE hypoxic responses occurred after Ro-32-0432 [86.2 +/- 6.2 ml/min in room air to 104.1 +/- 7.1 ml/min in 10% O2; pre- vs. post-Ro32-0432, P < 0.001 (analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilatory reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.
Gozal
D
D
Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. dgozal@tmcpop.tmc.tulane.edu
Graff
G R
GR
Torres
J E
JE
Khicha
S G
SG
Nayak
G S
GS
Simakajornboon
N
N
Gozal
E
E
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006935:Hypercapnia / Q000201:enzymology / Q000503:physiopathology*; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D019579:Neocortex / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012123:Pulmonary Ventilation / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C085989:Ro 32-0432; D011493:Protein Kinase C